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Stress-induced premature senescence may be involved in the pathogeneses of acute liver injury. Hexavalent chromium [Cr(VI)], a common environmental pollutant related to liver injury, likely leads to premature senescence in L02 hepatocytes. However, the underlying mechanisms regarding hepatocyte premature senility in Cr(VI) exposure remain poorly understood. In this study, we found that chronic exposure of L02 hepatocytes to Cr(VI) led to premature senescence characterized by increased β-galactosidase activity, senescence-associated heterochromatin foci, G1 phase arrest, and decreased cell proliferation. Additionally, Cr(VI)-induced senescent L02 hepatocytes showed upregulated inflammation-related factors, such as IL-6 and fibroblast growth factor 23 (FGF23), which also exhibited reactive oxygen species (ROS) accumulation derived from mitochondria accompanied with increased concentration of intracellular calcium ions (Ca2+) and activity of nuclear factor kappa B (NF-κB). Of note is that ROS inhibition by N-acetyl-Lcysteine pretreatment not only alleviated Cr(VI)-induced premature senescence but also reduced the elevated intracellular Ca2+, activated NF-κB, and secretion of IL-6/FGF23. Intriguingly, the toxic effect of Cr(VI) upon premature senescence of L02 hepatocytes and increased levels of IL-6/FGF23 could be partially reversed by the intracellular Ca2+ chelator BAPTA-AM pretreatment. Furthermore, by utilizing the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that NF-κB mediated IL-6/FGF23 to regulate the Cr(VI)-induced L02 hepatocyte premature senescence, whilst the concentration of intracellular Ca2+ was not influenced by PDTC. To the best of our knowledge, our data reports for the first time the role of ROS-Ca2+-NF-κB signaling pathway in Cr(VI)-induced premature senescence. Our results collectively shed light on further exploration of innovative intervention strategies and treatment targeting Cr(VI)-induced chronic liver damage related to premature senescence.

Background In recent years, ER+ and HER2- breast cancer of adjuvant therapy has made great progress, including chemotherapy and endocrine therapy. We found that the responsiveness of breast cancer treatment was related to the prognosis of patients. However, reliable prognostic signatures based on ER+ and HER2- breast cancer and drug resistance-related prognostic markers have not been well confirmed, This study in amied to establish a drug resistance-related gene signature for risk stratification in ER+ and HER2- breast cancer. Methods We used the data from The Cancer Genoma Atlas (TCGA) breast cancer dataset and gene expression database (Gene Expression Omnibus, GEO), constructed a risk profile based on four drug resistance-related genes, and developed a nomogram to predict the survival of patients with I-III ER+ and HER2- breast cancer. At the same time, we analyzed the relationship between immune infiltration and the expression of these four genes or risk groups. Results Four drug resistance genes (AMIGO2, LGALS3BP, SCUBE2 and WLS) were found to be promising tools for ER+ and HER2- breast cancer risk stratification. Then, the nomogram, which combines genetic characteristics with known risk factors, produced better performance and net benefits in calibration and decision curve analysis. Similar results were validated in three separate GEO cohorts. All of these results showed that the model can be used as a prognostic classifier for clinical decision-making, individual prediction and treatment, as well as follow-up.